Project Summary/Abstract Metabolic syndrome is a constellation of cardiovascular risk factors including abdominal obesity, atherogenic dyslipidemia, hypertension, insulin resistance, and a pro-inflammatory and pro-thrombotic state. A major risk factor for type 2 diabetes and early-onset cardiovascular disease, metabolic syndrome affects an estimated 25% of Americans. Metabolic syndrome traits differ among ethnic groups. African-Americans tend to have greater insulin-resistance and higher blood pressure than European-Americans; conversely, European- Americans have more atherogenic lipid profiles. In African-Americans, some metabolic syndrome traits correlate with African ancestry (insulin resistance, blood pressure), and others traits correlate with European ancestry (visceral fat, low HDL cholesterol, high triglycerides), suggesting that distinct genetic variants modulating these traits have been inherited from the two ancestral populations. We hypothesize that genetic loci underlying metabolic syndrome traits can be identified by admixture mapping in African- Americans. Admixture mapping is a genome-wide approach for identifying disease-associated genetic variants, which have a high allele frequency difference between ancestral populations. Admixture loci share linkage disequilibrium with ancestry-informative markers across large genomic segments and can be mapped using relatively few genetic markers, compared to genome-wide association studies. We propose to perform admixture mapping for all metabolic syndrome traits in a combined cohort of 2000 African-Americans from the Cardiovascular Health Study (CHS) and the Health, Aging and Body Composition Study (HABC). We will validate our findings via joint analyses with admixture mapping results from the Jackson Heart Study (JHS). We will perform admixture mapping for the following quantitative traits, individually and after principal component analysis: abdominal fat, obesity, fasting glucose and insulin, triglycerides, HDL and LDL cholesterol, serum inflammatory and thrombotic markers, and blood pressure. We will specifically focus on the role of abdominal visceral fat in metabolic syndrome by comparing results from mapping MetS traits with and without adjusting for visceral fat burden. Visceral fat measurement is uniquely available in HABC and JHS, and the collaboration between HABC and JHS will provide a novel and unique opportunity to identify genetic loci affecting metabolic syndrome traits independently of the profound effect of visceral fat. We will validate findings in joint analyses of the two independent cohorts. Our final goal is to perform fine mapping for the 4-6 most promising candidate loci among the traits analyzed to identify the underlying causative variants. Dissection of genetic influences on metabolic syndrome traits in a large ancestry-admixed cohort will illuminate the etiology of population differences in metabolic syndrome characteristics and prevalence and lay the foundation for research into population-specific management and treatment.